Substituted phenyl-carbamoyl-alkyl carbonylamino-benzimidazoles

ABSTRACT

Substituted benzimidazoles of the formula   IN WHICH R1 is alkyl, X is oxygen or sulfur, R2 is haloalkyl or haloalkenyl and R3, R4 and R5 each are hydrogen, halogen or alkyl, are valuable as systemic fungicides and as anthelmintic agents.

United States Patent [191 Dransch et al.

[ June 3, 1975 [73] Assignee: Hoechst Aktiengesellschaft,

Frankfurt am Main, Germany [22] Filed: Mar. 15, 1973 21 Appl.No.:34 1,760

[30] Foreign Application Priority Data Mar. 21, 1972 Germany 2213553 [52] US. Cl 260/309.2; 424/273 [51] Int. Cl C07d 49/38 [58] Field of Search 260/3092 [56] References Cited UNITED STATES PATENTS 3,541,213 11/1970 Klopping ..260/309.2

12/1971 Soboczenski et al. 260/3092 8/1973 Osieka et a1. 260/3092 OTHER PUBLICATIONS Littler, Chem. Abst., Vol. 73, N0. 2992f (1970),

' Primary Examiner-Natalie Trousof Attorney, Agent, or F irmCurtis, Morris & Safford [57] ABSTRACT Substituted benzimidazoles of the formula H MN , lma-000R R5 1 I z (EC-li g in which R is alkyl, X is oxygen or sulfur, R is haloalkyl or haloalkenyl and R R and R each are hydrogen, halogen or alkyl, are valuable as systemic fungicides and as anthelmintic agents.

9 Claims, N0 Drawings SUBSTITUTED PI-IENYL-CARBAMOYL-ALKYL CARBONYLAMINO-BENZIMIDAZOLES The present invention relates to benzimidazoles of the formula J qua-coca,

I II KN) R H with an isocyanate of the formula -R III b. a benzimidazole derivative of formula II with a carbamic acid halide of formula c. a chloro-(or bromo)-carbonylbenzimidazole derivative of formula J-Nn-comz with an amine of formula X-RZ H; N-@ R3 In the formulae, R preferably stands for alkyl or alkenyl having 2 or 3 carbon atoms, R R R preferably represent hydrogen, chlorine, methyl, and more preferably R, and R are hydrogen and R is methyl.

Corresponding to formulae II and V, the following compounds can be used, for example, as starting materials for the manufacture of compounds of formula I: 2-methoxy-, 2-ethoxy-, 2-n-propoxy-, 2-isopropoxy-, 2-n-butoxy-, 2-isobutoxy-carbonylaminobenzimidazoles; 4- or 5-methyl-, 4- or 5-ethyl-, 4- or 5- propyl-, 4- or 5-sec-butyl-, 4- or 5-tert.butyl-, 4- or 5- chloro-, 4- or 5-bromo-, 4,5-dichloro-, 4,6-dimethyl-, 4,5-dimethyl-, 5-chloro-6-methyl-, 5-chloro-6-butyl-, 6-chloro-5-propyl-2-methoxy-(ethoxy, prop0xy-, butoxy-) carbonylamino-benzimidazoles or the corresponding chloro-carbonyl-benzimidazoles of formula V. Preferred compounds are those in which R, and R are hydrogen.

Suitable compounds to be reacted with the above starting compounds are compounds of formulae III, IV, or VI in which R is substituted at least once by fluorine, chlorine or bromine. In particular, R may have the following meanings: p-, m-, or o-difluoromethoxy or -difluoromethylmercapto, p-, m-, o-l,l,2,2,- tetrafluoro-ethoxy or -ethylmercapto, 0-, m-, or pl,l,2,-trifluoro-4-chloro-ethoxy or -ethylmercapto, 0-, m-, p-l,2-dichloro-vinyloxy or -vinylmercapto, 0-, m-, p-1,l ,2,3,3,3-hexafluoro-propoxy or -propylmercapto, por m-l,l-difluoro-2-bromo-2-fluoro-ethoxy of -ethylmercapto, por m-l,l-difluoro-2-fluoro-2- chloro-ethoxy or -ethylmercapto, o-, m-, p-2-chloroethoxy or -ethylmercapto, o-, m-, p-3-bromo-propoxy 0r -propylmercapto, o-, m-, p-3,3-dichloro-2- propcnyloxyor -propenylmercapto, o-, m-, p-2,3,3,- trichloro-2-propenyloxy or -propenylmercapto, o-, m-, p-l,2-dibromo-vinyloxy or vinyl-mercapto, p- ,4,-hexafluoro-3-chloro-2-butenyl-(2)-0Xy- 0r -mercapto.

Preferably preferred compounds of formulae III, IV or VI are those which contain a halo-substituted alkoxy or alkyl-mercapto group having 11 2 or 3 carbon atoms and from among them those having 2 n f orine and/or chlorine and/or bromine atoms and fi p ltion to X a hydrogen atom, as well as those havmg an ,2-dichlorovinyl group in R position.

The starting compounds and their reactants are P y n, partly they can be prepared by known methods (cf. for example J. Am. Soc. 56. page 144 US Pat. No. 2,933,502).

The nitro compounds necessary for the preparation of the amines were obtained in a manner similar to the methods described in J. Am. Soc. 70, page 593 (1948); nd. Engineering Chem. 39, page 412 (1947); J. Org. Chem 25, p ge 2009 (1960), and Bull. Soc. Chim. Belges P ge 270 (1965), and transformed into the amines according to conventional methods.

Several of the amines could be synthesized directly according to the method of Bull. Soc. Chim. France, 5, page 581 (1957).

The amines thus obtained were converted according to the usual methods into the carbamic acid halides or isocyanates.

The process according to (a) is preferably carried out in an inert organic solvent, for example dimethyl formamide, methylethyl ketone, methylene chloride, chloroform, chlorobenzene, tetrahydrofurane, or acetonitrile, at a temperature in the range of from about 5 to 50C. It is advantageous to use a small excess of isocyanate. The reaction periods are, in general, I to 8 hours.

When operating according to process (b) the carbamic acid chloride of formula IV is first prepared by adding, at 0 to 25C, an amine of formula VI to a solution of phosgene in an inert organic solvent, such as benzene or tetrahydrofurane, separating from the hydrochloride of the amine by filtration and distilling off the excess phosgene under reduced pressure. An approximately stoichiometric amount of a 2-alkoxycarbonyl-amino-benzimidazole derivative of formula II and subsequently an acid-binding agent, for example a tertiary amine or potassium carbonate are then added. In this stage of the reaction the temperature is generally in the range of from 0 to 35C. The reaction mixture is worked up in usual manner.

According to process (0) a 2-alkoxycarbonylaminobenzimidazole derivative of formula II is treated with a solution of phosgene in an inert organic solvent at about to +20C, then an equivalent amount of a tertiary amine, for example dimethyl-aniline, triethylamine, or pyridine, is added and the hydrochloride is separated. After having distilled off the excess phosgene the reaction product is reacted with twice the stoichiometric amount of an amine of formula VI at about 0 to 40C and the mixture is worked up in usual manner.

The compounds according to the invention are char acterized by very good fungicidal properties, and especially by a very broad range of action. As they have a very low toxicity to warm blooded animals and not only a protective but also a curative systemic effect, they are especially suitable to protect plants, above all in agriculture.

Owing to their systemic activity the compounds of the invention can be used for combating fungus diseases on plants by either seed treatment, soil treatment or foliar treatment.

A number of fungi against which the compounds are effective are listed below:

E rysiphe cichoracearum Piricularia oryzae Pellicularia sasakii Fusarium nit-ale Rhizocraniu solam' Verlicilluni alboairum Fusarizmi .rolani Bolrylis cincrea ()idium tuckeri Cerz'aspara beticola Cercospora musae Uromyces plias'eoli Seplorio apii Podos/zaera leucotricha Vcnluria inaequalis The compounds of formula I can also be used for combating parasitic diseases of warm blooded animals, especially helminths.

They exhibit an especially pronounced anthelminthic activity, combined with a good compatibility, against stronyles parasitic in the alimentary tract mainly of ruminants. These parasites may cause great economical damange in animal breeding. Hence, the compounds of the invention represent valuable medicines. In practice, the anthelminthic agents are administered orally or subcutaneously. For oral administration ready suspensions (l to 50 percent, preferably 3 to 15 percent strength) water suspendable powders (concentration 1 to percent, preferably 40 to 70 percent), pastes or granules of different concentrations are used. For parenteral treatment sterile solutions of different concentrations are suitable. To achieve a good distribution, stabilization and conservation of the'active ingredient as well as an improved resorption additives are necessary, preferably talc, lactose, magnesium stearate, starch, or polyethylene glycol or finely dispersed silicic acid.

The following examples illustrate the invention, Examples l to 21 being concerned with the preparation of benzimidazoles according to the invention, while the following examples illustrate their fungicidal effect. In the latter biological examples l-butylcarbamoyl-Z- methoxycarbonyl-aminobenzimidazole, (common name benomyl) was used as the most closely related commercial product. In comparison to benomyl, the compounds of formula I are equally good or even better in their effect when used in the same concentrations by weight; they are more effective, however, when molar concentrations are compared.

EXAMPLE 1 a. Preparation of p-nitrophenyl-difluoromethyl sulfide used as precursor 168 Grams of p-nitrothiophenol were added to the solution of 250 g of sodium hydroxide in 285 ml of water and 370 ml of ethylene glycol dimethyl ether and at 70-80C 130 g of difluorochloromethane were introduced into the suspension while stirring. After cooling, 500 ml of water and 200 ml of ether were added to the suspension, the whole was filtered, the ether phase was separated and the aqueous phase extracted three times, each time with 200 ml of ether. The combined ether extracts were dried over potassium carbonate, freed from solvent under reduced pressure and the p-nitrophenyl-difluoromethyl sulfide was distilled at 9093C/0.05 mmHg.

b. Preparation of paminophenyl-difluoromethyl sulfide used as precursor The suspension of 106 g of p-nitrophenyldifluoromethyl sulfide, 245 g of iron powder and 2 ml of glacial acetic acid in 1.7 liters of water was stirred for 10 hours at -90C, after cooling it was filtered and the residue washed with 200 ml of benzene. The aqueous phase was extracted twice, each time with 200ml of benzene, soda was added to adjust a pH of l l and the iron oxide was filtered off. It was washed with benzene and the aqueous phase was again extracted with 200 ml of benzene. The combined benzene extracts were dried over potassium carbonate, the benzene was distilled first and then the p-aminophenyldifluoromethyl sulfide; boiling point 84C/0.l mm Hg.

c. Preparation of p-difluoromethyl-mercaptophenyl isocyanate used as reactant A solution of 63 g of p-aminophenyl-difluoromethyl sulfide in 100 ml of chlorobenzene was dropped at l0C into a solution of 150 g of phosgene in 400 ml of chlorobenzene and, while introducing a weak current of phosgene, the temperature was raised to 130C within 8 hours. When the reaction was terminated, the phosgene in excess was removed from the clear solution by a nitrogen current and the solution was freed from chlorobenzene under reduced pressure. The pdifluoro-methyl-mercaptophenyl isocyanate was then distilled at 76-78C/0.3 mm Hg.

d. 1-(4-difluoromethylmercapto)-phenylcarbamoyl-2- methoxycarbonylamino-benzimidazole reaction product dried under reduced pressure. 34 Grams of l-(4-difluoromethylmercaptophenylcarbamoyl)-2-methoxy-carbonylaminobenzimidazole (87 percent of the theory) were ob- 5 tained, decomposition point 326C.

C H N O S (392.4). Y Cale: C, 52.05%; H, 3.59%; F, 9.68%; N, 14287. found: C, 52.00%; H, 3.5%; F, 9.9%; N, 14.30%.

EXAMPLE 2 l-[3-( 1,1 ,2,2-tetrafluoroethoxy)-phenylcarbamoyl]-2- methoxycarbonylamino-benzimidazole 19.1 Grams of 2-methoxycarbonylaminobenzimidazole were suspended in 600 ml of chloroform and to the suspension 24.1 g of 3-( l,1,2,2-tetrafluoroethoxy)-phenyl isocyanate were added. The suspension was stirred for 7 hours at room temperature, heated at 40C and undissolved matter was separated by filtra- 20 tion. The chloroform solution was concentrated under reduced pressure and the remaining 1-[3-(1,1,2,2- tetrafluoro-ethoxy)-phenylcarbamoyl]-2-methoxycarbonylamino-benzimidazole was washed with gasoline. The crystals were dried at room temperature under reduced pressure. Yield 32 g (78 percent of the theory);

decomposition point 295C.

C H F N O (426.3). 02110.: C, 50.72%; H, 3.30%; F, 17.82%; N, 13.14%. found: C, 50.8%; H, 3.0%; F, 17.7%; N, 12.9%. In analogous manner the compounds listed in the following Table were obtained.

1 A B L E Example Formula Decomposition Analysis point (00) 02.10 found 0 54.2 c 55.9 520 5.72 H 5.7 0= ':-NH- -0cF H 10.09 F 10,0 14.09 N 14,8

N I 54,26 0 54,0 4 J -Nn-coocn 309 5.72 n 5.7 10.09 F 10.2 14.89 N 14.7 001 ,11

N 49.72 C 4-9. 5 5 j-im-cooczn 320 5.19 H 5.1 0= ':-NH- -OCF2H P 9. 24 F 9, 5 15. 64 N 15, 7

N 55.58 c 55.2 s v i N l -NH-COOCH 325 4. 15 H 4. 2 o=t':-Nn- 700F211 9.72 F 9,0 14.55 N 14.6

T A B L E Continued Example Formula fi g f Analysis I point i v (c) 0810. found Q J 52.05 c 51.9

-mrr-cooc H9 13 4.15 H 4.0 0=CNH 11.76 F 11.7

0CF -CHFCl 11,56 N 11,4

Hac A 49.96 c 50.0

- -NH-COOCH l8 (H56) a 282 H 5.4 0=CNH- 12.48 F 12,4

' A isomer mixture ,0 ocF,-cHF'c1 12.27 N 12.4

, H cm 51,05 0 50,8 -NH-COOCH Y 0CF -CHFCl .9 N 12.1

' Q NH coocrr- C 2O (C1) 1? 3 1 0 .74 H 2,7 O=Cr-NH- l F 11. 7

11 ifiomer mixture 0CF2-CHFC1 11-74 N .5

-NH--COOCH I 21 c1 a 210 5 H 2,2 O=C-NH-@ 11 14 F 11. 3 A OCF -CHFCi -.95 N 11.0

EXAMPLE 22 Plants of cucumbers in the two-leaf stage were strongly infested with conidia of cucumber mildew- Erysiphe cichoracearumand 5 days after infestation the plants were sprayed to the drip-off with spray liquors containing per liter 100, 50, 25, 12.5, 6, and 3 milligrams, respectively, of active compound. As comparative compound the benzimidazole derivative 1- 0 butylcarbamoyl-2-methoxy-carbonylaminobenzimidazole (benomyl) wasused in the same concentrations. After drying of theflayer of active ingredient, the plants were placed in a] greenhouse where they were kept at C and -90 percent of relative atmospheric humidity. After a period of 14 days the plants were examined as to their infestation with mildew. The result, expressed as degree of effectiveness in percent, is listed in Table I.

Compound r of R. AR2 Example R curative effect against cucumber mildew in 74mm of active ingredient 00F, -CFC1H' i ocF,-cHF

T A B L E I (cont) Compound R Curative effect against of R A 2 cucumber mildew in i ippm Z R3 of active ingredient 14 o-cc1=cc1H 100 100 100 97 95 9o OCF2-CC12H -CH 12 9 100 100 100 97 95 9o OCF -CCl H o-cF -CFH-CF5 O-CF CHFBr comparafive benomyl 100 100 98 95 9o 85 compound untreated O o O O O 0 EXAMPLE 23 grown to the four-leaf stage. The plants were then strongly infested with conidia of powdery mildew of wheat. After an incubation time of 10 days the plants were examined as to their infestation with mildew, the leaves which had not been treated with the active ingredient being taken for evaluation. The results indicated in Table II show that the compounds of the invention had the same effect as the comparative substance benomyl, although, calculated on the effective molecule, the content of active ingredient was much lower.

TABLE II of wheat; application in 2-leaf Exar-1p.-.a stage; infestation in 4-leaf stage Compound. X R effect in 71 against mildew of ppm of active ingredient OCF CFC1H 2 Q 100 95 90 85 7 00F CHF2 .6 H 100 90 85 so 5 'OCFZ H 100 .97 95 90 14 -0-CC1=CC1H 100 100 97 95 9 9 Q 100 100 97 p 95 9o 12 100 100 100 98 95 00F -cc1 H 1o Q Cclz H 100 100 100 97 95 -cF -CFH-CF3 11 (DZ "CHClz 100 100 97 90 009 -CHFBr comparative benomyl 1 O0 100 95 90 85 compound untreated 0 o o o 0 EXAMPLE 24 cation of the spray liquor, the plants were placed in the greenhouse and when the third and fourth leaves had Cucumber plants 1n the tw0-leaf stage were treated developed the plants were strongly infested with co- Wlth the Compounds llsted in Table III in concentm- 65 nidia of cucumber mildew. 14 Days after infestation the lions 5 i and 60 i igrams plants were examined as to their infestation with milof active ingredient per liter of spray liquor in a manner dew. The result, calculated in percent of effectiveness, such that only the two fully developed leaves, but not calculated on infested surface of the leaves, is listed in the other portions of the plant became wet. After applithe following Table III.

T A B L E III Compound v effect; in 71: against cucumber 01 R mildew; application in 2-leaf Example P stage; infestation in 4-leaf 5 stage; ppm of active ingredient OCF -CFClH OCF -CHF s 100 100 90 e5 6o 14 -OCC1=CC1H 100 100 95 90 80 7o OCF -CCI H CH5 l2 100 100 97 90 75 OCF CCl H 1o -O CF2 CC1H 100 100 97 9o 85 75 o-cF -CFHCF OCF -CHFBI comparative benomyl 100 98 95 9o 85 75 compound untreated O O O O O 0 EXAMPLE 25 liquor. Benomyl was used as comparative compound in the same concentrations. After drying of the layer of house at 20C and high relative atmospheric humidity above 80 pe'rc ent suitable for the growth of Oidium. After an incubation time of 14 days, theplants were examined as to their-infestation with Oidium. The result in percent of effectiveness is listed in Table IV.,

active ingredient, the plants were placed in the green- C mpost soil was treated and thoroughly mixed with the mpounds listed in Table V in an amount of 5, 2,5, 1.25, 0.6, and 0.3 milligrams per kilogram oi soil. The soil was rilled in pots having a diameter of 10 T A B L E IV Comzgun R 2 effect in 7': against Oidium on vine with curative treatment Example, R 5 days after infestation with 3 ppm of active ingredient OCF -CFclH OCF -CHFz ,14 -O-CCl=CCl H 100 100 95 9o so 70 9 Q 100 100 97 95 9O 8O 75 OCF CC1 H 11 100 95 90 so 75 7o OCF -CHFBr comparabemmyl 100 98 9o 85 so 70 65 compound untreated O O o O O o 0 EXAMPLE 26 cm and 2 cucumber seeds were sown in each pot, 5 pots being used for each test.

After emergence of the cucumber plants they were strongly infested in the two-leaf and four-leaf stage with conidia of cucumber mildew (Erysiphe cichoracearum) and the infested plants were placed overnight in an infestation chamber with 100 pcrceni relative zitinom m f 14. days, h plums WCYC examined as m spheric humidity at 20C Subsequently, the plants were kept in the greenhouse at 20C and a relative attheir infcslation with mildew The results expressed as degree of effectiveness in percent are indicated in 5 Table V.

mospheric humidity of 85-90 percent. After an incuba- T ABLE O 5 O 5 5 5 O no 8 8 00 00 no no r) O 5 0 8 oo 8 8 8 L e t m w 5 5 O 5 5 O 5 5 5 O m M 9 9 9 9 9 9 9 9 9 9 M u a 6 C e 1 r d 7 7 5 7 8 5 V 7 1% ,5 m 9 9 9 9 9 9 9 9 w w m MW NJ W W o i O s O O O O O O O O a r W m m m w J O O O O W W mm e i l l l l l l l i t m i O O O O O O O O O O O O J 0 O O O O O O O O O O O i v f l l l l l l l l 1 l l l c e 0 e d v N u m 0 O O O L 5 O O O O vQ O O 8 m p 1 0 O O O O O O O O 0 w w l 1 7 1 1 1 l 1 1 1! 1 H P H 2 c v H m H H m u 1 r j 2 2 2 C B Au m w w m n c F H w e i F D C C l .Tq 2 C C H H l C C 2 m E C Y a R w 2 2 C m m F 2 2 n m m 2 2 UL F C 2 5 2 C F F O. r X R F F C 5 C F H F m C (v 5 F H t C C O H O O C C C O u D H C e n O O m C 0 O n O m C O b v 1 O O O Q *0 Q f p i l R C d n e M .U u l 7 2 6 5 A 9 2 O 5 l 5 a n M m, l 1 l l l 1 w w m & W1: 9 o x m v m C E o i o c t c EXAMPLE 27 TABLE was used as comparative substance. After drying of the layer of active ingredient, the'plants were placed in a greenhouse at C and a relative atmospheric humidity of 80-90 percent. After an incubation time of 14 days, the plants were examined as to their degree of infestation with mildew. The result is indicated in the following Table VI.

Compound X41 effect in 95 against apple mildew of R 2 with curative treatment with Example R3 ppm of active ingredient OCF -CFClH ocr -cuF 14 O-CC1=CC1H 100 100 90 85 8O 75 OCF -CCl H OCF CCl H o-cF -CFHCF5 11 OCFBCHClZ 100 100 100 95 90 8o 70 OCF2CHFB1" compara- I I tive benomyl 100 100 98 9O 85 75 70 compound I 0 o o 0 untreated O O O EXAMPLE 2s Celery plants in the grown-up five-leaf stage were stongly infested with spores of Septoria apii and placed for one day in a moisture chamber at C. Thereafter, the plants were treated with the compounds listed in Table VII in concentrations of 500, 250, 125, 60, and

VII

T A B L E Compound X..R effect in") against Septoria.

of R @Z 2 apii in celery with prophylac- Example 3 tie treatment with ppm of active 5 ingredient OCF -CFC1H 2 Q 100 98 95 9O 8O OCF CHF l4 @-OCC1=CC1H 100 100 98 95 85 OCF -CCl H Cl v 15 Q 100 100 98 95 9O 11 'CHClz 100 100 95 90 ()CF -"HFBr comparehive benomyl 100 100 85 75 compound untreated 0 0 V O O 0 What is claimed is:

l. A benzimidazole of the formula in which R is alkyl of l to 4 carbon atoms,

X is oxygen or sulfur,

6. The compound of claim 1 having the formula 7. The compound of claim 1 having the formula chlorine, bromine, or alkyl of l to 4 carbon atoms, and if R, and R are different, mixtures thereof.

2. The compound of claim 1 were X is oxygen.

3. The compound of claim I having the formula Nil-COUCH OCF CC 1 H O=C-Nl-l- -OCF -CC 1 H 8. The compound of claim 1 having the formula -NH-COOCH O=C-NH- -CH O'CF -CC I H 9. The compound of claim l-having the formula -NH-COOCH O=C-Nl- -OCC1=CHC1 

1. A benzimidazole of the formula
 1. A BENZIMIDAZOLE OF THE FORMULA
 2. The compound of claim 1 were X is oxygen.
 3. The compound of claim 1 having the formula
 4. The compound of claim 1 having the formula
 5. The compound of claim 1 having the formula
 6. The compound of claim 1 having the formula
 7. The compound of claim 1 having the formula
 8. The compound of claim 1 having the formula 